Platelet factor 4 (PF4) is induced by klotho and rejuvenates cognition and its molecular signature in the aging hippocampus

Platelet factors regulate wound healing and also signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here, we show that systemic platelet factor 4 (PF4) modulates cognition and its molecular signature. Klotho, a longevity and cognition-enhancing protein, acutely activated platelets and increased circulating platelet factors, most robustly platelet factor 4 (PF4). To directly test PF4 effects on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In aging mice, PF4 restored cognitive deficits and rejuvenated a molecular signature of cognition in the aging hippocampus. Augmenting platelet factors such as PF4, a possible messenger of klotho, may enhance cognition in the young brain and rejuvenate cognitive deficits in the aging brain. Overall design: mRNA-seq data of hippocampus extracted from 3-5 months (young) or 17-20 months (old), vehicle- (Veh) or PF4-treated (PF4) mice (C57BL/6J) were generated by deep sequencing using Illumina sequencing.

血小板因子可调控伤口愈合，同时还能作为血液来源的信号传递至大脑。然而，血小板因子是否能够调控认知功能——这是大脑功能中极具价值且核心的表现——目前尚无定论。本研究证实，系统性血小板因子4（PF4）可调控认知功能及其分子特征。克洛素（Klotho）作为一种兼具延缓衰老与增强认知作用的蛋白质，可快速激活血小板并提升循环中的血小板因子水平，其中以血小板因子4（PF4）的上调最为显著。为直接验证PF4对大脑的调控作用，我们分别对小鼠施以赋形剂对照（vehicle）或系统性PF4处理。在年轻小鼠中，PF4可增强突触可塑性与认知能力；在老年小鼠中，PF4能够修复认知缺陷，并使衰老海马体中与认知相关的分子特征恢复年轻化状态。上调诸如PF4这类血小板因子——其可能作为克洛素的信号信使——或可增强年轻大脑的认知能力，并改善衰老大脑的认知缺陷。本研究整体实验设计如下：采用Illumina测序平台开展深度测序，获取来自3~5月龄（年轻）或17~20月龄（老年）C57BL/6J小鼠的海马体mRNA测序（mRNA-seq）数据，实验对象涵盖经赋形剂对照（Veh）或PF4处理的小鼠。